As part of an ongoing evaluation of human papillomavirus (HPV)- immortalized cervical epithelial cells, the recently developed HPV/Hras and HPV positive cervical carcinomas are being studied in in vitro models of cytokine and chemotherapeutic drug modulation of target cell sensitivity to natural killer (NK) and to lymphokine activated killer (LAK) lymphocyte cytotoxicity. Treatment of HPV-16 positive cervical epithelial cells with cisplatin and gamma-interferon or leukoregulin further influences the sensitivity of the cervical cells to LAK lymphocyte cytotoxicity. (51)Cr labeled HPV-16 immortalized CX16.2 cells, HPV-16 and H-ras sequentially transfected and tumorigenic PHI cells and HPV-16 positive QGU cervical carcinoma cells were treated for one hour with either 2 units of leukoregulin/ml or with 100 units gamma-interferon/ml in the presence of 10 nM cisplatin. The cells were incubated with 7 day IL-2-stimulated LAK lymphocytes for 4 hours at lymphocyte:cervical cell ratios from I to 10:1 and the net release of (51)Cr was measured. Cisplatin alone increased the sensitivity of CX16.2 cells to LAK lysis 1.2-fold as indicated by the increase in LU(20%)/10(6) LAK cells, but decreased the sensitivity of the PHI and QGU cells 1.4- 1.2-fold, respectively. Leukoregulin alone up-regulated the sensitivity of CXI6.2 cells 1.4-fold, PHI cells 1.7-fold and QGU cells 2.5-fold. Combined leukoregulin and cisplatin treatment produced a synergistic increase of 4.4-fold for the CXI6.2 and QGU and 2.4-fold for the PHI cells. Gamma-interferon alone or in combination with cisplatin was less effective than leukoregulin and usually produced neither an additive nor a synergistic increase in target cell sensitivity when used in combination with cisplatin. These results demonstrate that combination treatment with a cytokine and a chemotherapeutic agent has the potential to rapidly up- or down-regulate the sensitivity of HPV-16 positive dysplastic or neoplastic cervical epithelial cells to LAK lymphocyte cytotoxicity and that the addition of leukoregulin can overcome decreased target cell sensitivity to LAK lymphocyte killing produced by cisplatin.